The present invention relates to pharmaceutical agents (compounds) which act as 5-HT.sub.4 agonists or antagonists and/or 5-HT.sub.3 antagonists in mammals. As 5-HT.sub.4 agonists, these compounds are gastrointestinal prokinetic agents useful for the treatment of human gastrointestinal (GI) hypomotility disorders such as reflux esophagitis, gastroparesis, nonulcer dyspepsia, ileus, constipation and irritable bowel syndrome (constipation predominant). As 5-HT.sub.4 antagonists these compounds are useful in the treatment of motility disorders of the GI tract such as diarrhea and irritable bowel syndrome (diarrhea predominant). As 5-HT.sub.3 antagonists these compounds are useful in slowing colonic transport and therefore are useful in the treatment of diarrhea predominant irritable bowel syndrome. The 5-HT.sub.4 agonists or antagonists and/or 5-HT.sub.3 antagonists are also useful in the treatment of emesis, anxiety, visceral pain, substance abuse (either cravings or withdrawal syndrome), cognitive disorders and other CNS disorders wherein treatment with a serotonin 5-HT.sub.4 agonists or antagonists and/or 5-HT.sub.3 antagonists would be indicated.
Serotonin (5-hydroxytryptamine; 5-HT) functions as a neurotransmitter in the mammalian central nervous system (CNS) and in the periphery. Serotonin is unsurpassed among monoamine neurotransmitters in the number of receptor subtypes identified. To date, the number of subtypes is into the teens, including the major subtypes 5-HT1A, 1B, 1C, 1D, 1E, 2A, 2B, 3 (perhaps subtypes), 1P, serotonin transporter, etc. Because of the multiplicity of serotonin receptor subtypes, the identification of which serotonin receptor subtype is correlated to various physiological/pharmacological actions is complicated.
Serotonin has been known for some years to promote peristalsis in the GI tract in various animal models. During the mid 1980s, several specific antagonists to the 5-HT.sub.3 receptor subtype were identified from independent laboratories. These 5-HT.sub.3 antagonists were shown to be prokinetic in various rodent models. Hence, many publications and patents have issued wherein 5-HT.sub.3 antagonists are claimed to be useful as GI prokinetic agents to treat various human hypomotility states: reflux esophagitis, nonulcer dyspepsia, gastroparesis, ileus, irritable bowel syndrome.
Gunning and Naylor (J. Pharm. Pharmacol. 1985, 37, 78) reported that metoclopramide (a 5-HT.sub.3 antagonist which blocks the 5-HT.sub.3 -mediated Bezold Jarisch reflex) enhanced electrical-field stimulated contractions in guinea pig stomach strips. Simultaneously, Buchheit et al (J. Pharm. Pharmacol. 1985, 37, 664) reported that three 5-HT.sub.3 antagonists [metoclopramide, ICS-205930, and MDL 72222] both enhanced guinea pig stomach muscle strip contraction in vitro and led to increases in gastric emptying rates in vivo. H. Kimura et al (Jpn. J. Pharmacol., 49 (suppl.) Mar. 25-28, 1989, 196pp) independently reported that SN-307, a selective 5-HT.sub.3 antagonist, enhanced transit of a charcoal meal in mice. J. S. Gidda et al (Gastroenterology 1988, 95, A867) reported that several 5-HT.sub.3 antagonists [ICS-205930, GR38032, and zacopride] enhanced gastric emptying. From these reports it was logically concluded that serotonin 5-HT.sub.3 antagonists would be useful agents for the therapeutic treatment of human GI dysmotilities where restoration of peristalsis and enhancement of transit is indicated.
More recently several clinical reports indicate that 5-HT.sub.3 antagonists do not accelerate GI transit in man. Talley et al (Digestive Diseases and Sciences 1989, 34, 1511) has reported that GR38032, a selective 5-HT.sub.3 antagonist, did not alter small intestinal transit times or mouth-to-cecum transit times. The conclusion was that GR38032 does not have a major effect on GI transit in man. Another clinical report by S. Gore et al (Aliment. Pharmacol. Therap. 1990, 4, 139) has demonstrated that GR38032 not only failed to accelerate GI transit, but in fact slowed colonic transit in man. Thus while 5-HT.sub.3 antagonists do accelerate GI transit in rodent species (guinea pig, mouse, rat), they do not affect small bowel transit in man, and decrease, rather than increase, colonic transit.
Canine models of GI transit may more accurately reflect human results. J. M. Van Nueten et al (British J. Pharmacology, 1989, 96, 331P) reported recently that cisapride (a reported 5-HT.sub.3 antagonist) enhanced antroduodenal motility in dogs, whereas ICS-205930, another potent 5-HT.sub.3 antagonist did not. Moreover, ICS-205930 did not affect the responses to cisapride when the agents were coadministered. Nemeth and Gullikson (European J. Pharmacology, 1989, 166, 387) reported that the ability of BRL-24924 and cisapride to depolarize myenteric neurons was unrelated to their properties of 5-HT.sub.3 antagonism.
The receptor mechanism by which cisapride, BRL-24924, metoclopramide, and other serotonergic agents are prokinetic is not related to their 5-HT.sub.3 antagonist properties. The receptor mechanism responsible for their prokinetic activities is serotonergic, but at a serotonin receptor subtype, presently referred to as 5-HT.sub.4. (M. Tonini et al Pharmacological Research, 1991, 24, 5).
Initially this clarification came from the laboratory of A. Dumuis, M. Sebben and J. Bockaert (Naunyn-Schmiedeberg's Arch. Pharmacol 1989, 340, 403). The prokinetic activity of a variety of benzamides, including cisapride and BRL-24924, were found to correlate with agonist activity at a novel 5-HT.sub.4 receptor subtype identified in mouse embryonic colliculi neurons. Shortly thereafter, D. Craig and D. Clarke identified the 5-HT.sub.4 receptor in the myenteric plexus of the guinea pig ileum (J. Pharmacol. Exp. Ther., 1990, 252, 1378). Quite recently Craig and Clarke also demonstrated that the peristaltic reflex evoked by serotonin and the benzamide BRL-24924 (renzapride) was mediated through agonism at 5-HT.sub.4 receptors. The compounds of the present invention exhibit potent activity in a 5-HT.sub.4 agonism in vitro functional assay compared to its epimer and previously disclosed compounds.
E. A. Watts (U.S. Pat. No. 4,816,453 1989) discloses N-heterocyclic derivatives of benzamides useful in treating gastric and intestinal disorders and as 5-HT.sub.3 antagonists including the following compounds hereinafter referred to as B-#1 and B-#2: ##STR3## As is shown in the 5-HT.sub.4 agonism assays described herein, the compounds of the present invention show superior 5-HT.sub.4 agonist activity over B-#1 and B-#2.
There is a need in the area of serotonin regulation for agents with broad clinical usefulness. Serotonin is one of the newer neurotransmitters to be recognized for physiological importance and agents which interact with 5-HT receptors are currently the focus of much research. P. Bonate, Clinical Neuropharmacology, Vol. 14, No. 1, pp. 1-16 (1991).
Accordingly, it is the object of this invention to produce compounds for use as pharmaceutical agents which will exhibit 5-HT.sub.4 agonist or antagonist and/or 5-HT.sub.3 antagonist activity in mammals. The compounds of the present invention meet the need for an agent which has broad clinical usefulness for treating conditions affected by 5-HT.sub.4 agonists or antagonists and/or 5-HT.sub.3 antagonists in mammals by administering therapeutically effective amount of the compounds.